CHEMICAL LIBRARY SCREENING CORE 1. MAIN OBJECTIVES AND DIRECTIONS The mission of the Chemical Library Screening (CLS) Facility Core is to provide new chemical tools and potential drug develop to Neuroscience investigators. The utility of small molecule screening for solving problems in biology is illustrated by a number of recent reports in the literature (see citations below). It is also anticipated that this route of study will provide assay and chemical inputs into the pipeline for the development of new lead molecules for the treatment of neurological disorders. Since high-throughput screening is not widely available at academic institutions, this facility will provide a new and unique approach toward characterizing proteins and signaling pathways involved in many aspects of neural development and neurologic disease. This Core will be located at the Burnham Institute for Medical Research (BIMR) and represents an expansion of an existing Core that was developed by BIMR's Cancer Center, but is not available to neuroscientists at this time. BIMR's contribution to this grant is represented by the institutional purchase of equipment, including the robotic screening facility, high-throughput microscopes, and chemical libraries, valued at well over $2 million. The proposed NIH Blueprint Neuroscience Core Center Grant will facilitate and encourage use of this Chemical Screening Core by neuroscientists on the La Jolla Torrey Pines Mesa at BIMR, The Salk Institute, The Scripps Research Institute (TSRI), and the University of California, San Diego (UCSD). The Core facility will offer chemical libraries, including an integrated robotic line with an automated incubator, plate hotel and tip loader, for biochemical assays with readouts including FRET, fluorescence polarization, and luminescence. Also offered is a complete high content screening line that includes robotics for liquid and plate handling, automated incubator, plate hotel in a clean-room environment for cell-based assays. Image-acquisition capabilities include Beckman Coulter and GE automated microscopes with robotic plate feeding. Sophisticated software packages are used for automated tracking of plates and compounds, cheminformatics, and image analysis. In general, two kinds of screens are performed with the following nomenclature: (i) HTS is high throughput screening, typically used for biochemical screens or plate-reader screens of cell-based assays;(ii) HCS is high content screening, used for image-based screens of cell assays, i.e. type of assays that use image analysis of cells. Expert assistance is available for all aspects of biochemical and cell-based screens, including automation engineering, medicinal chemistry, image acquisition, algorithm engineering and analysis. The CLS facility is located at BIMR within the San Diego Chemical Genomics Center (SDCGC), which also operates as one of the 9 NIH funded extramural centers of the Multiple Library Screening Center Network. The center is directed by Dr. Mark Mercola and managed by Dr. Steve Vasile. Dr. Mercola also directs Assay Development and Assay Implementation units of the SDCGC. Currently, the CLS facility operates as a charge-back basis to support members of the BIMR Cancer Center under the auspices of the BIMR Cancer Center Support Grant (CCSG). Because of heavy demand, it has offered only very limited and occasional service to members of the Cancer research community not at BIMR, and virtually no access to neuroscientists. The primary goal of this application is to provide salary support for personnel within CLS to support and facilitate interdisciplinary, collaborative research projects of neuroscience investigators on the La Jolla Torrey Pines Mesa.